Original articleRegional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis
Introduction
Velocardiofacial syndrome (VCFS) is a relatively common genetic disorder that affects between 1:2000 and 1:5000 individuals (du Montcel et al 1996). Caused by a microdeletion on chromosome 22q.11 Driscoll et al 1992, Edelmann et al 1999, Scambler et al 1992, the syndrome is associated with multiple anomalies, including cardiac defects, cleft palate, a characteristic facial appearance, pharyngeal structural abnormalities leading to hypernasal speech, language deficits, attentional deficits, executive domain dysfunction, and learning disabilities Golding-Kushner et al 1985, Moss et al 1999, Shprintzen et al 1978, Swillen et al 1997. The behavioral and psychiatric phenotype associated with VCFS includes disinhibition, impulsivity, schizoid features, and flat affect (Papolos et al 1996). Between 10% and 30% of patients with VCFS develop severe psychiatric illness during late adolescence (Shprintzen et al 1992), including schizophrenia Bassett and Chow 1999, Pulver et al 1994a, Pulver et al 1994b and bipolar disorder (Papolos et al 1996). Murphy et al (1999), for example, evaluated a cohort of 50 adults with VCFS, and found that 30% had a psychotic disorder, with 24% of those individuals meeting the criteria for schizophrenia. In addition, 12% of the total cohort had symptoms that fulfilled the criteria for major depression without psychosis.
Little is known about how the 22q.11 deletion affects brain development, ultimately producing the neurocognitive and neuropsychiatric phenotype that is characteristic of VCFS patients. Initial qualitative reports of MRI findings in these patients described the presence of smaller than normal cerebellar vermi, brainstem and posterior fossa, enlarged sylvian fissure, cysts adjacent to the anterior ventricular horns, and white matter hyperintensities Altman et al 1995, Bingham et al 1997, Mitnick et al 1994. Only recently have quantitative, volumetric neuroimaging studies been initiated Amelsvoort et al 1999, Chow et al 1999, Eliez et al 2000, which are critical to our understanding of neuroanatomic development in VCFS. In a preliminary study of ten adults with VCFS and ten matched controls, (Amelsvoort and coworkers 1999) reported that subjects with VCFS had significantly smaller cerebellum and occipital lobes, larger parietal lobes, and loss of ventricular asymmetry. In a recently published study by Eliez et al (2000), the authors compared 15 children and adolescents with VCFS to 15 matched controls, and found that in children with VCFS, white matter was reduced to a greater extent (16.3%) than gray matter (7.5%), frontal lobe tissue was relatively preserved, and parietal lobe gray matter was significantly reduced.
Contributing to that growing literature, we report here the results of an anatomic MRI study in which we compared the relative proportions of gray matter and white matter in major lobar regions of the brains of ten children with VCFS and ten age- and gender-matched controls. We first hypothesized that white matter would be specifically compromised in VCFS. This hypothesis was based on the assumption that the T2 hyperintensities that have been found in patients with VCFS represent the presence of white matter anomalies even in brains where white matter lesions have not been clinically recognized. The neurocognitive phenotype that characterizes VCFS formed the basis of our second hypothesis, which was that the frontal lobe (implicated in ADHD and in disorders of executive function) (Mega and Cummings 1994) and the parietal lobe (a component of the “attentional network” as well as a substrate of visuospatial perception, which is often compromised in children with VCFS) Moss et al 1999, Posner and Peterson 1990 would be particularly affected in this disorder. The neuropsychiatric phenotype associated with VCFS formed the basis of the third hypothesis, which was that in addition to the frontal lobe, the temporal lobe which is altered in schizophrenia (Pearlson and Marsh, 1999) may also be altered in VCFS.
Section snippets
Sample
The sample, ranging in age from 7.9 to 14.5 years, consisted of ten children with VCFS (seven girls and three boys), mean age 10.1 (SD, 1.8); mean IQ, 73 (SD, 15.0); and ten unaffected children, individually matched by age and gender, mean age 10.1(SD, 1.9); mean IQ, 96.6 (SD 10.4). The study was explained to all participants in language appropriate to their level of cognitive functioning. Each participant and parent signed a consent form that met the institutional review board standards of the
Results
The gray, white, and total cerebral tissue volumes of children with VCFS were somewhat, but not significantly, smaller than that of their age-matched peers (total cerebral tissue: 8.5% difference; cerebral gray: 7% difference; cerebral white: 10.7% difference). No significant differences were found between the two groups in the volume of CSF. To determine whether the magnitude of volume reductions in parietal, temporal, or occipital regions exceeded reductions in total cerebral volumes,
Discussion
This investigation suggests that children with VCFS have significantly reduced tissue volumes in nonfrontal lobar regions of the brain. These volume reductions seem to affect nonfrontal white matter to a greater extent than nonfrontal gray matter. In the right hemisphere, reductions in white matter seem to be distributed relatively evenly throughout all of the posterior lobar regions. In the left hemisphere, white matter in the left parietal and temporal lobes seem disproportionately reduced
Acknowledgements
This work was supported by a Young Investigator Award from the National Alliance for Research in Schizophrenia and Depression (WRK) and National Institutes of Health Grants Nos. HD 24061, P60 DE13078, and M01 RR00052 (EWJ).
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